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Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids.

ABSTRACT: A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ?III-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ?III and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ?III.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6600541 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids.

Zhao Yu Y Wang Tian-En TE Mills Alberto A Gago Federico F Fang Wei-Shuo WS

Molecules (Basel, Switzerland) 20190608 11

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and βIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both βIII and P-gp, among which compound <b ...[more]

PMID: 31181726

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